• Contrast enhanced MRI of liver or kidneys in patients with high suspicion or evidence of having focal lesions to classify these lesions as benign or malignant.

• Contrast enhancement in magnetic resonance angiography (CE-MRA).

Gadovist can also be used for MR Imaging of pathologies of the whole body.

It facilitates visualisation of abnormal structures or lesions and helps in the differentiation between healthy and pathological tissue.

Gadovist should be used only when diagnostic information is essential and not available with unenhanced magnetic resonance imaging (MRI).

4.2 Posology and method of administration

Gadovist should only be administered by healthcare professionals experienced in the field of clinical MRI practice.

Method of administration

This medicinal product is for intravenous administration only.

The dose required is administered intravenously as a bolus injection. Contrast-enhanced MRI can commence immediately afterwards (shortly after the injection depending on the pulse sequences used and the protocol for the examination).

Optimal signal enhancement is observed during arterial first pass for CE-MRA and within a period of about 15 minutes after injection of Gadovist for CNS indications (time depending on type of lesion/tissue).

Intravascular administration of contrast media should, if possible, be done with the patient lying down. After the administration, the patient should be kept under observation for at least half an hour, since experience shows that the majority of undesirable effects occur within this time (see section 4.4).

Instructions for use:

This product is intended for single use only.

This medicinal product should be visually inspected before use.

Gadovist should not be used in case of severe discolouration, the occurrence of particulate matter or a defective container.

Prefilled syringes

The prefilled syringe must be taken from the pack and prepared for the injection immediately before the administration.

The tip cap should be removed from the prefilled syringe immediately before use.

Cartridges

Administration of contrast media should be performed by qualified personnel with the appropriate procedures and equipment.

Sterile technique must be used in all injections involving contrast media.

The contrast medium must be administered by means of a MEDRAD Spectris® type injector.

Instructions of the device manufacturer must be followed.

• Posology

The lowest dose that provides sufficient enhancement for diagnostic purposes should be used. The dose should be calculated based on the patient's body weight, and should not exceed the recommended dose per kilogram of body weight detailed in this section.

Adults

CNS indications

The recommended dose for adults is 0.1 mmol per kilogram body weight (mmol/kg BW). This is equivalent to 0.1 ml/kg BW of the 1.0 M solution.

If a strong clinical suspicion of a lesion persists despite an unremarkable MRI or when more accurate information might influence therapy of the patient, a further injection of up to 0.2 ml/kg BW within 30 minutes of the first injection may be performed.

Whole Body MRI (except MRA)

In general, the administration of 0.1 ml Gadovist per kg body weight is sufficient to answer the clinical question.

Gadovist should only be used in patients with severe renal impairment (GFR < 30 ml/min/1.73m2) and in patients in the perioperative liver transplantation period after careful risk/benefit assessment and if the diagnostic information is essential and not available with non-contrast enhanced MRI (see section 4.4). If it is necessary to use Gadovist, the dose should not exceed 0.1 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Gadovist injections should not be repeated unless the interval between injections is at least 7 days.

Paediatric population

For children of all ages (including term neonates) the recommended dose is 0.1 mmol gadobutrol per kg body weight (equivalent to 0.1 ml Gadovist per kg body weight) for all indications (see section 4.1).

Neonates up to 4 weeks of age and infants up to 1 year of age

Due to immature renal function in neonates up to 4 weeks of age and infants up to 1 year of age, Gadovist should only be used in these patients after careful consideration at a dose not exceeding 0.1 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Gadovist injections should not be repeated unless the interval between injections is at least 7 days.

Elderly (aged 65 years and above)

No dosage adjustment is considered necessary. Caution should be exercised in elderly patients (see section 4.4).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

While injecting Gadovist into veins with a small lumen there is the possibility of adverse effects such as reddening and swelling.

The usual safety requirements for magnetic resonance imaging, especially the exclusion of ferromagnetic materials, also apply when using Gadovist.

Hypersensitivity reactions

As with other intravenous contrast agents, Gadovist can be associated with anaphylactoid/hypersensitivity or other idiosyncratic reactions, characterized by cardiovascular, respiratory or cutaneous manifestations, and ranging to severe reactions including shock. In general, patients with cardiovascular disease are more susceptible to serious or even fatal outcomes of severe hypersensitivity reactions.

The risk of hypersensitivity reactions may be higher in case of:

• previous reaction to contrast media

• history of bronchial asthma

• history of allergic disorders

In patients with an allergic disposition the decision to use Gadovist must be made after particularly careful evaluation of the risk-benefit ratio.

Most of these reactions occur within half an hour of administration. Therefore, post-procedure observation of the patient is recommended.

Medication for the treatment of hypersensitivity reactions as well as preparedness for institution of emergency measures are necessary (see section 4.2).

Delayed reactions (after hours up to several days) have been rarely observed (see section 4.8).

Impaired renal function

Prior to administration of Gadovist, it is recommended that all patients are screened for renal dysfunction by obtaining laboratory tests.

There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of some gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment (GFR < 30 ml/min/1.73 m2). Patients undergoing liver transplantation are at particular risk since the incidence of acute renal failure is high in this group.

As there is a possibility that NSF may occur with Gadovist, it should therefore only be used in patients with severe renal impairment and in patients in the perioperative liver transplantation period after careful risk/benefit assessment and if the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI).

Haemodialysis shortly after Gadovist administration may be useful at removing Gadovist from the body. There is no evidence to support the initiation of haemodialysis for prevention or treatment of NSF in patients not already undergoing haemodialysis.

Neonates and infants

Due to immature renal function in neonates up to 4 weeks of age and infants up to 1 year of age, Gadovist should only be used in these patients after careful consideration.

Elderly

As the renal clearance of gadobutrol may be impaired in the elderly, it is particularly important to screen patients aged 65 years and older for renal dysfunction.

Seizure disorders

Like with other gadolinium containing contrast agents special precaution is necessary in patients with a low threshold for seizures.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose (based on the average amount given to a 70 kg person), i.e. essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of gadobutrol in pregnant women. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3).

Gadovist should not be used during pregnancy unless the clinical condition of the woman requires use of gadobutrol.

Breast-feeding

Gadolinium containing contrast agents are excreted into breast milk in very small amounts (see section 5.3). At clinical doses, no effects on the infant are anticipated due to the small amount excreted in milk and poor absorption from the gut. Continuing or discontinuing of breast feeding for a period of 24 hours after administration of Gadovist, should be at the discretion of the doctor and lactating mother.

Fertility

Animal studies do not indicate impairment of fertility.

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

The overall safety profile of Gadovist is based on data from more than 6,300 patients in clinical trials and from post-marketing surveillance.

Delayed anaphylactoid reactions (hours later up to several days) have been rarely observed (see section 4.4).

Most of the undesirable effects were of mild to moderate intensity.

The adverse drug reactions observed with Gadovist are represented in the table below. They are classified according to System Organ Class (MedDRA). The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Adverse drug reactions from clinical trials are classified according to their frequencies.

Frequency groupings are defined according to the following convention: common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1,000 to < 1/100; rare: ≥ 1/10,000 to < 1/1,000. The adverse drug reactions identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under 'not known'.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

0 Injection site reactions (various kinds) comprise the following terms: Injection site extravasation, injection site burning, injection site coldness, injection site warmth, injection site erythema or rash, injection site pain, injection site hematoma

Patients with an allergic disposition suffer more frequently than others from hypersensitivity reactions.

Fluctuations of renal function parameters including increases of serum creatinine have been observed after administration of Gadovist.

Paediatric population

Based on two single dose phase I/III studies in 138 subjects aged 2-17 years and 44 subjects aged 0-<2 years (see section 5.1) the frequency, type and severity of adverse reactions in children of all ages (including term neonates) are consistent with the adverse drug reaction profile known in adults. This has been confirmed in a phase IV study including more than 1,100 paediatric patients and postmarketing surveillance.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

No signs of intoxication from an overdose have so far been reported during clinical use.

In case of inadvertent overdosage, cardiovascular monitoring (including ECG) and control of renal function is recommended as a measure of precaution.

In case of overdose in patients with renal insufficiency, Gadovist can be removed by haemodialysis. After 3 haemodialysis sessions approx. 98 % of the agent are removed from the body. However, there is no evidence that haemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF).

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Paramagnetic contrast media,

ATC code: V08C A09

Mechanism of action

The contrast-enhancing effect is mediated by gadobutrol, the nonionic complex consisting of gadolinium(III) and the macrocyclic ligand dihydroxy-hydroxymethylpropyl-tetraazacyclododecane-triacetic acid (butrol).

Pharmacodynamic effects

In clinical doses, gadobutrol leads to shortening of the relaxation times of protons in tissue water. At 0.47 T (20 MHz), pH 7 and 40 °C the paramagnetic effect (relaxivity), as determined from the effect on spin-lattice relaxation time (T1) measured in plasma - is about 5.6 l mmol-1 sec-1 and the spin-spin relaxation time (T2) is about 6.5 l mmol-1 sec-1. Within the range 0.47 to 2.0 Tesla, the relaxivity displays only slight dependency on the strength of the magnetic field.

With high local tissue concentrations of gadobutrol the T2 effect results in a lessening of signal intensity.

Clinical efficacy

In a pivotal phase III liver study average sensitivity in combined pre and post-contrast MRI for Gadovist-treated patients was 79 % and specificity was 81 % for lesion detection and classification of suspected malignant liver lesions (patient based analysis).

In a pivotal phase III kidney study average sensitivity was 91 % (patient-based analysis) and 85 % (lesion-based analysis) for classification of malignant and benign renal lesions. Average specificity in a patient-based analysis was 52 % and in a lesion-based analysis 82 %.

The increase of sensitivity from pre-contrast to combined pre and post-contrast MRI for Gadovist-treated patients was 33 % in the liver study (patient-based analysis) and 18 % in the kidney study (patient-based analysis as well as lesion-based analysis). The increase in specificity from pre-contrast to combined pre and post-contrast MRI was 9 % in the liver study (patient based analysis) while there was no increase in specificity in the kidney study (patient-based analysis as well as lesion-based analysis).

All results are average results obtained in blinded reader studies.

In a study designed as an intra-individual, crossover comparison, Gadovist was compared to gadoterate meglumine (both at 0.1 mmol/kg) in the visualization of cerebral neoplastic enhancing lesions in 132 patients.

The primary efficacy endpoint was the overall preference for either Gadovist or gadoterate meglumine by the median blinded reader. Superiority of Gadovist was demonstrated by a p-value of 0.0004. In detail, a preference of Gadovist was given for 42 patients (32 %) compared to an overall preference for gadoterate meglumine for 16 patients (12 %). For 74 patients (56 %) no preference for one or the other contrast agent was given.

For the secondary variables lesion-to-brain ratio was found to be statistically significantly higher for Gadovist (p < 0.0003). Percent of enhancement was higher with Gadovist compared to gadoterate meglumine, with a statistical significant difference for the blinded reader (p < 0.0003).

Two single dose phase I/III studies in 138 paediatric subjects scheduled for CE-MRI of CNS, liver and kidneys or CE-MRA and in 44 subjects aged 0-<2 years (including term neonates) scheduled to undergo routine CE-MRI of any body region have been performed. Diagnostic efficacy and an increase in diagnostic confidence was demonstrated for all parameters evaluated in the studies and there was no difference among the paediatric age groups and when compared to adults. Gadovist was well tolerated in these studies with the same safety profile of gadobutrol as in adults.

5.2 Pharmacokinetic properties

Distribution

After intravenous administration, gadobutrol is rapidly distributed in the extracellular space. Plasma protein binding is negligible. The pharmacokinetics of gadobutrol in humans are dose proportional. After doses up to 0.4 mmol gadobutrol/kg body weight, the plasma level declines in a biphasic manner. At a dose of 0.1 mmol gadobutrol/kg BW, an average of 0.59 mmol gadobutrol/l plasma was measured 2°minutes after the injection and 0.3 mmol gadobutrol/l plasma 60 minutes post injection.

Biotransformation

No metabolites are detected in plasma or urine.

Elimination

Within two hours more than 50 % and within 12 hours more than 90 % of the given dose is eliminated via urine with a mean terminal half-life of 1.8 hours (1.3 – 2.1 hours), corresponding to the renal elimination rate. At a dose of 0.1 mmol gadobutrol/kg BW, an average of 100.3 ± 2.6 % of the dose was excreted within 72 h after administration. In healthy persons renal clearance of gadobutrol is 1.1 to 1.7 ml min-1 kg-1 and thus comparable to the renal clearance of inulin, pointing to the fact that gadobutrol is eliminated primarily by glomerular filtration. Less than 0.1 % of the dose is eliminated via faeces.

Characteristics in special patient populations

Paediatric population

Pharmacokinetics of gadobutrol in paediatric population aged < 18 years and in adults are similar (see section 4.2).

Two single dose phase I/III studies inpaediatric patients < 18 years have been performed. The pharmacokinetics were evaluated in 130 paediatric patients aged 2 -< 18 years and in 43 paediatric patients <2 years of age (including term neonates).

It was shown that the pharmacokinetic (PK) profile of gadobutrol in children of all ages is similar to that in adults resulting in similar values for area under the curve (AUC), body weight normalized plasma clearance (CLtot) and volume of distribution (Vss), as well as elimination half-life and excretion rate.

Approximately 99% (median value) of the dose was recovered in urine within 6 hours (this information was derived from the 2 to <18 year old age group).

Elderly (aged 65 years and above)

Due to physiological changes in renal function with age, in elderly healthy volunteers (aged 65 years and above) systemic exposure was increased by approximately 33 % (men) and 54 % (women) and terminal half-life by approximately 33 % (men) and 58 % (women). The plasma clearance is reduced by approximately 25 % (men) and 35 % (women), respectively. The recovery of the administered dose in urine was complete after 24 h in all volunteers and there was no difference between elderly and non-elderly healthy volunteers.

Renal impairment

In patients with impaired renal function, the serum half-life of gadobutrol is prolonged due to the reduced glomerular filtration. The mean terminal half-life was prolonged to 5.8 hours in moderately impaired patients (80>CLCR>30 ml/min) and further prolonged to 17.6 hours in severely impaired patients not on dialysis (CLCR<30 ml/min). The mean serum clearance was reduced to 0.49 ml/min/kg in mild to moderately impaired patients (80>CLCR>30 ml/min) and to 0.16 ml/min/kg in severely impaired patients not on dialysis (CLCR<30 ml/min). Complete recovery in the urine was seen in patients with mild or moderate renal impairment within 72 hours. In patients with severely impaired renal function about 80 % of the administered dose was recovered in the urine within 5 days (see also sections 4.2 and 4.4).

In patients requiring dialysis, gadobutrol was almost completely removed from serum after the third dialysis.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

Repeated intravenous treatment in reproductive toxicology studies caused a retardation of embryonal development in rats and rabbits and an increase in embryolethality in rats, rabbits and monkeys at dose levels being 8 to 16 times (based on body surface area) or 25 to 50 times (based on body weight) above the diagnostic dose in humans. It is not known whether these effects can also be induced by a single administration.

Single and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk for use in children of all ages including term neonates and infants.

Radioactively labelled gadobutrol administered intravenously to lactating rats was transferred to the neonates via milk at less than 0.1 % of the administered dose.

In rats, absorption after oral administration was found to be very small and amounted to about 5 % based on the fraction of the dose excreted in urine.

In preclinical cardiovascular safety pharmacology studies, depending on the dose administered, transient increases in blood pressure and myocardial contractility were observed. These effects have not been observed in humans.

Environmental studies have shown that persistence and mobility of GBCAs indicates a potential for distribution in the water column and possibly into groundwater.

6. Pharmaceutical particulars

6.1 List of excipients

Calcobutrol sodium

Trometamol

Hydrochloric acid 1N (pH-adjustment)

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

3 years (prefilled syringe)

3 years (cartridge)

Shelf life after first opening of the container:

Any solution for injection not used in one examination must be discarded. Chemical, physical and microbiological in-use stability has been demonstrated for 24 hours at 20-25°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions after first opening of the medicinal product, see section 6.3.

Any contrast medium solution not used in one examination must be discarded.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

The peel-off tracking label on the pre-filled syringes/cartridges should be stuck onto the patient record to enable accurate recording of the gadolinium contrast agent used. The dose used should also be recorded. If electronic patient records are used, the name of the product, the batch number and the dose should be entered into the patient record.